A 3-month-old male domestic short-hair kitten was presented with chronic constipation and disproportionate dwarfism. Radiographs of the long bones and spine revealed delayed epiphyseal ossification and epiphyseal dysgenesis. Diagnosis of congenital primary hypothyroidism was confirmed by low serum total thyroxine and high thyroid stimulating hormone concentrations. Appropriate supplementation of levothyroxine was instituted. The kitten subsequently developed mild renal azotaemia and renal proteinuria, possibly as a consequence of treatment or an unmasked congenital renal developmental abnormality. Early recognition, diagnosis and treatment are vital as alleviation of clinical signs may depend on the cat's age at the time of diagnosis.

The purpose of this study case report was to describe the diagnosis, treatment and outcome of a dwarf kitten diagnosed with primary congenital hypothyroidism that subsequently developed renal azotaemia during treatment. Possible pathomechanisms for the renal insufficiency are discussed.

Ethical consideration

This is a case report describing a clinical case of a client-owned pet presenting to the Onderstepoort Veterinary Academic Hospital (OVAH). The animal reported was treated and housed according to the standard OVAH protocols for the management of client-owned pets. All diagnostic tests were performed as part of the work-up. No diagnostic tests or treatments were conducted for research purposes.

Informed consent

The owner of the cat reported here has given written consent for publishing purposes.

Case presentation

A 3-month-old male domestic short-hair kitten weighing 1.2 kg was presented with chronic constipation of 6 weeks' duration. An obviously small for age and disproportionate stature was noted. All four limbs and tail were short and stubby, whilst the head was broad with flattened facial features (Figure 1a). The coat was dry and oral examination revealed only a few semi-erupted incisor teeth and marked macroglossia. The abdomen was moderately distended with palpable firm faecal balls in the colon. Thoracic auscultation was within normal limits. Rectal temperature was mildly subnormal (37.3 °C). On neurologic examination, mental dullness and proprioceptive ataxia manifesting as a 'bunny-hopping' gait were detected.

In this case, disproportionate dwarfism was the most striking feature. Causes of congenital feline dwarfism include endocrinopathies such as hypothyroidism, hypopituitarism, juvenile diabetes mellitus and hypoadrenocorticism. Non-endocrine causes included portosystemic vascular anomalies, renal disease, osteochondrodysplasia, cardiac defects and lysosomal storage diseases (Johnson & Watson 2010). Malnutrition and gastrointestinal diseases were less likely causes of dwarfism based on the history and absence of vomiting and/or diarrhoea. Pituitary dwarfism was also considered unlikely as affected animals demonstrate proportionate dwarfism (Johnson & Watson 2010).

Treatment was initiated with levothyroxine 50 µg PO q 24h (Eltroxin®, Aspen Pharmacare) administered with food and lactulose 1 mL PO q 12h (Laxette®, Cipla Medpro) for 6 weeks. Marked improvement of the kitten's facial conformation from the originally broad head and flattened facial features to a more 'pointy' muzzle and lower jaw was noted on follow-up. The kitten was also more active. As expected, TT4 increased and TSH reduced over the months of follow-up (Table 1). The levothyroxine dose was adjusted accordingly. Up to 8 months of age, TT4 remained subnormal and TSH markedly elevated, likely as a result of the 'overdrive' effect of prolonged decreased TT4 on the pituitary. By 11 months of age, the kitten became polyuric and polydipsic with mild renal azotaemia and hyperphosphataemia, borderline proteinuria (urine protein to creatinine [UPC] ratio 0.32, RI 0.2-0.4) and inadequately concentrated urine (urine specific gravity [USG] 1.024). Abdominal ultrasound revealed hyperechoic renal cortices with poor corticomedullary definition. Systolic/diastolic blood pressure measurements were within normal limits at 125/89 mmHg. These findings were suggestive of non-hypertensive, borderline proteinuric, International Renal Interest Society stage 2 chronic renal insufficiency. The levothyroxine dose was further increased and thyroid and renal values monitored. Serial serum TT4, TSH, urea, creatinine, UPC and USG showed progressive improvement, with normalisation of all parameters over time, except for mild renal azotaemia, which persisted. Follow-up radiographs at 26 months of age (Figures 2c and 3b) revealed complete closure of the physes of the vertebrae and long bones, ossification of the carpal and tarsal bones and resolution of the spina bifida occulta. At the time of submission of the last draft of the manuscript the patient was 41 months old, led a normal life and was on a levothyroxine dose of 150 µg in the morning and 100 µg at night (Figure 1b).

Thyroid hormones are essential for normal postnatal development of the skeletal and nervous systems (Greco 2006; Scott-Moncrieff 2007). Bone growth is influenced by thyroid hormone via two mechanisms, (1) stimulation of growth hormone production by the pituitary gland and (2) interaction with growth hormone to balance the sequence of growth cartilage production-degeneration and regulation of endochondral ossification until physeal closure (Saunders & Jezyk 1991). Therefore, delayed epiphyseal ossification and epiphyseal dysgenesis with disproportionate dwarfism are the hallmarks of congenital hypothyroidism (Greco 2006). An absolute definitive diagnosis of hypothyroidism requires a TSH or TRH stimulation test (Gunn-Moore 2005).

Thyroid hormones influence renal tubular function and electrolyte absorption or secretion, mitochondrial enzymes and neural renal functions (Braunlich 1984; Mariani & Berns 2012) and therefore hypothyroidism can have a negative influence on renal function (Van Hoek & Daminet 2009). Hypothyroidism may lead to decreased protein synthesis and cellular development decreasing functional renal mass, density and size (Canavan et al. 1994; Slotkin et al. 1992). Alteration of renal function in humans (Den Hollander et al. 2005) and dogs (Gommeren et al. 2009) via direct and indirect effects has been well documented. The direct effects include intrarenal and peripheral vascular vasoconstriction (Singer 2001), decreased response to vasodilators in the kidney (Den Hollander et al. 2005) and decreased activity of the renin-angiotensin-aldosterone system (Asmah et al. 1997), all of which result in decreased renal blood flow. The indirect effects on renal function relate to decreased cardiac output (Katz, Emmanouel & Lindheimer 1975), leading to further decreased glomerular filtration rate (GFR) and increased serum creatinine (Capasso et al. 1999; Den Hollander et al. 2005). Hypothyroidism in dogs that have been shown to have reduced GFR is at least partially reversible by re-establishing euthyroidism (Gommeren et al. 2009). In hypothyroid dogs, improvement of renal function is observed with thyroxine supplementation, and a strong correlation between changes in thyroid status, serum creatinine concentration and GFR have been reported (Den Hollander et al. 2005; Gommeren et al. 2009). A recent study in cats demonstrated that hypothyroid cats had significantly higher plasma creatinine concentrations than euthyroid cats (Williams et al.2010). To the best of the authors' knowledge, renal insufficiency in feline congenital hypothyroidism has never been reported. It is believed that in this case the low thyroid concentration could have affected kidney development and function as a result of reduced GFR, with reduced metabolism and excretion of creatinine (Van Hoek & Daminet 2009). Interestingly, children with congenital hypothyroidism have reduced renal mass and a higher prevalence of renal and urologic abnormalities such as dysplastic kidneys (Kumar et al. 2009). Moreover, it is believed that the growth and a concomitant increase in muscle mass in the kitten led to an increase in creatinine production. This, together with inadequate restoration of euthyroidism by an inadequate dose of levothyroxine, caused mild renal azotaemia to persist until approximately 12 months of age. Subsequent increases in the doses of levothyroxine were accompanied by a steady rise in TT4concentrations with resultant reductions in the concentrations of TSH and the consequent establishment of euthyroidism. It is further postulated that the concomitant increment in USG, the reduction of serum creatinine and the normalisation of the UPC ratio from the time when euthyroidism was established support the assertion that inadequate establishment of euthyroidism played a role in the renal azotaemia in the patient. Although this could not be proven as no GFR evaluation was performed, it has been shown to occur in dogs and humans. In fact, a recent human study lends credence to the above argument as it demonstrated that children with acquired hypothyroidism had significantly lower GFR than normal children for up to 5 years after the start of thyroxine treatment and the restoration of euthyroidism (Elgadi et al. 2008). Further renal histopathology and GFR evaluation would have been indicated, but was unfortunately not performed. Renal histopathology would not have changed treatment decisions and the proteinuria normalised when euthyroidism was attained.

Cats with congenital hypothyroidism treated with levothyroxine should have a normal life expectancy as long as treatment is not stopped, but the long-term prognosis is unknown (Feldman & Nelson 2004; Szabo & Wells 2007) and is dependent on aetiology and age of initiation of treatment (Bojanicet al. 2011). The findings in this case indicate that early diagnosis and timing of treatment can reverse the typical clinical signs and improve skeletal development. An important finding in this case is that the dose of sodium levothyroxine needs to be in the range of 30 µg/kg bid in order to establish euthyroidism, which is much higher than the 10 µg/kg - 20 µg/kg bid recommended for dogs. An improvement in activity is expected within the first weeks of treatment and the remaining dermatological, cardiovascular and neurological signs should improve after weeks to months of treatment, as was seen in this case. At the time of reporting the cat's constipation, polyuria and polydipsia had completely resolved.

This is the first reported case of feline primary congenital hypothyroidism with concomitant renal insufficiency.

Acknowledgements

Competing interests

The authors declare that they have no financial or personal relationship(s) that may have inappropriately influenced them in writing this article.

Authors' contributions

C.K.L. (University of Pretoria) was the primary author and was responsible for the imaging interpretations, collaborating work of co-authors and writing the manuscript. C.T.R. (University of Pretoria) helped in medical interpretations and contributed intellectually to the manuscript preparation and in its writing. Y.d.W. (University of Pretoria) was the owner of the kitten as well as the primary veterinary nurse responsible for care, observation and diagnostic work-up of the kitten. J.P.S. (University of Pretoria) was the primary clinician responsible for diagnosis and follow-up of the case and contributed intellectually to the manuscript.